Abstract
In the present study, the association between angiopoietin-like 4 (ANGPTL4) and aldolase A (ALDOA) in human melanoma cell invasion and survival was investigated. Overexpression and knockdown of ANGPTL4 were respectively performed in WM-115 and WM-266-4 cells. ALDOA expression at both the mRNA and the protein levels as well as the ALDOA gene promoter activities were increased and decreased in parallel with overexpression and knockdown of ANGPTL4 in the melanoma cells, which was blocked by selective protein kinase C (PKC) inhibitor and restored by PKC agonist, respectively. ANGPTL4 overexpression significantly increased cell invasion and matrix metalloproteinase-2 (MMP-2) expression and decreased cell apoptosis against cisplatin in WM-115 cells, which was reversed by knocking down ALDOA. In WM-266-4 cells, knockdown of ANGPTL4 decreased cell invasion and MMP-2 expression and increased cell apoptosis against cisplatin, which was reversed by overexpression of ALDOA. In conclusion, this study demonstrates that ANGPTL4 upregulates ALDOA expression in human melanoma cells at the ALDOA gene promoter/transcriptional level through a PKC-dependent mechanism, and that ALDOA is a critical mediator of the promoting effect of ANGPTL4 on melanoma cell invasion, likely through upregulating the MMP-2 expression. Additionally, our results suggest that ALDOA plays an important role in ANGPTL4-enhanced melanoma cell survival against apoptotic stress, which implicates ANGPTL4 and ALDOA in the development of melanoma chemoresistance.
Highlights
A novel approach to therapeutic strategy is emerging, which based on the peculiar metabolism of cancer cells
Western blot analysis showed that stable transfection of angiopoietin‐like 4 (ANGPTL4) led to an over two‐fold increase of ANGPTL4 expression in WM‐115 cells, which was not affected by selective protein kinase C (PKC) inhibitor Go6983 (500 nM)
The aldolase A (ALDOA) expression in WM‐115 cells increased in parallel with ANGPTL4 overexpression, which was inhibited by Go6983
Summary
A novel approach to therapeutic strategy is emerging, which based on the peculiar metabolism of cancer cells. Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source, exceeding the capacity of mitochondrial oxidative energy metabolism [1]. The three aldolase isozymes (ALDOA, ALDOB and ALDOC) have a tetramer structure with identical molecular weights of ~160 kDa. It is well known that cancer cells with a high glycolytic rate often exhibit an aberrant expression of all glycolytic enzymes [2]. It has been found that the control of glycolysis in rapidly growing tumor cells occurs at least partly at the level of the consuming block (from aldolase to lactate dehydrogenase) [3]. A previous study has suggested that aldolase is involved in melanoma cell survival [1]
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